The metabolic cofactor Coenzyme A enhances alternative macrophage activation via MyD88-linked signaling
Jones, A. E.; Rios, A.; Ibrahimovic, N.; Chavez, C.; Bayley, N. A.; Ball, A. B.; Hsieh, W. Y.; Sammarco, A.; Bianchi, A. R.; Cortez, A. A.; Graeber, T. G.; Hoffmann, A.; Bensinger, S. J.; Divakaruni, A. S.
Show abstract
Metabolites and metabolic co-factors can shape the innate immune response, though the pathways by which these molecules adjust inflammation remain incompletely understood. Here we show that the metabolic cofactor Coenzyme A (CoA) enhances IL-4 driven alternative macrophage activation [m(IL-4)] in vitro and in vivo. Unexpectedly, we found that perturbations in intracellular CoA metabolism did not influence m(IL-4) differentiation. Rather, we discovered that exogenous CoA provides a weak TLR4 signal which primes macrophages for increased receptivity to IL-4 signals and resolution of inflammation via MyD88. Mechanistic studies revealed MyD88-linked signals prime for IL-4 responsiveness, in part, by reshaping chromatin accessibility to enhance transcription of IL-4-linked genes. The results identify CoA as a host metabolic co-factor that influences macrophage function through an extrinsic TLR4-dependent mechanism, and suggests that damage-associated molecular patterns (DAMPs) can prime macrophages for alternative activation and resolution of inflammation.
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